Facile one-pot synthesis of 4-hydroxy-2-methyl-(2H)-1,2-benzothiazine-3- sulfonic acid 1,1-dioxide

Article abstract of DOI:10.1080/00397910601131437

We report a convenient synthesis of 4-hydroxy-2-methyl-(2H)-1,2- benzothiazine-3-sulfonic acid-1,1-dioxide (6a) prepared in a novel one-pot reaction. The synthesis involves two transformations starting from 2-methyl-2H-1,2-benzothiazin-4-(3H)-one 1,1-dioxide (7) with an overall yield better than that from the stepwise process, as well as the alternate procedure starting from saccharin (1). One-pot synthesis of an important intermediate, saccharin-N-methane sulfonic acid (4), is also described. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910601131437

Synthetic Communicationsw, 37: 767–773, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910601131437
Facile One-Pot Synthesis of 4-Hydroxy-2-
methyl-(2H)-1,2-benzothiazine-3-sulfonic
Acid 1,1-Dioxide
Waseeq A. Siddiqui
Department of Chemistry, Government College University,
Lahore, Pakistan
Saeed Ahmad
Applied Chemistry Research Center, Pakistan Council of Scientific &
Industrial Research Laboratories Complex, Lahore, Pakistan
Islam Ullah Khan
Department of Chemistry, Government College University,
Lahore, Pakistan
Hamid Latif Siddiqui
Institute of Chemistry, University of the Punjab, Lahore, Pakistan
George W. Weaver
Department of Chemistry, Loughborough University, Loughborough, UK
Abstract: We report a convenient synthesis of 4-hydroxy-2-methyl-(2H)-1,2-ben-
zothiazine-3-sulfonic acid-1,1-dioxide (6a) prepared in a novel one-pot reaction. The
synthesis involves two transformations starting from 2-methyl-2H-1,2-benzothiazin-
4-(3H)-one 1,1-dioxide (7) with an overall yield better than that from the stepwise
process, as well as the alternate procedure starting from saccharin (1). One-pot
Received July 24, 2006
Address correspondence to Saeed Ahmad, Applied Chemistry Research Center,
PCSIR Laboratories Complex, Ferozepur Road, Lahore, Pakistan. E-mail:
malikdrsaeed@yahoo.com
767

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W. A. Siddiqui et al.
synthesis of an important intermediate, saccharin-N-methane sulfonic acid (4), is
also described.
Keywords: 1,2-benzothiazine-3-sulfonic acid 1,1-dioxide, chloromethyl saccharin,
hydroxymthyl saccharin, 2-methyl-4-oxo-1,2-benzothiazine, saccharin N-methanesul-
fonic acid
In recent years there has been rapid growth in the number of publications
dealing with the 1,2-benzothiazine-1,1-dioxide ring system.[1–3] Much of
the literature pertains to the discovery that 3-carboxamides of 4-hydoxy-2-
alkyl-2H-1,2-benzothiazine-1,1-dioxide are anti-inflammatory and antirheu-
matic agents, which include piroxicam.[4] In connection with our ongoing
research program to develop new anti-inflammatory agents, we needed
4-hydroxy-2-methyl-(2H)-1,2-benzothiazine-3-sulfonic acid 1,1-dioxide
(6a). To the best of our knowledge, no work has been reported on such
compounds, and therefore this article forms the base of these studies.
First, we carried out the preparation of saccharin-N-methane sulfonic acid
(4) in a three-step process (hydroxymethylation, chlorination, and sulfonation)
where each step was studied separately with the idea of designing a one-pot
procedure. Reports on N-alkylation of sodium saccharin quoted yields up to
70% in aqueous phase in the literature.[5] We synthesized N-hydroxymethyl
saccharin (2) in up to 92% yield from insoluble saccharin (1) by reaction with
formaline (37%). Chlorination of (2) with thionyl chloride [6] under anhydrous
conditions afforded N-chloromethyl saccharin (3). Sulfonation of (3) was
achieved by treatment with sodium sulfite via an insitu iodomethyl deriva-
tive[7] to yield saccharin-N-methane sulfonic acid (4) in 45% yield.
On the basis of the knowledge developed in this process, the possibility of
direct conversion of (1) into (4) in one pot was explored. It afforded (4) in
good yield. The cleavage of the heterocycle in (4) was achieved by
treatment with sodium methoxide in methanol to get (5) in 83% yield. Cycli-
zation of the latter, followed by insitu N-methylation, accomplished the
synthesis of (6) in poor yield.
Further, we devised an excellent route to synthesize (6a) from 2-methyl-
2H-1,2-benzothiazin-4-(3H)-one 1,1-dioxide 7.[8] Bromination of (7) by
N-bromosuccinimide with azoisobutyronitrile[9] in carbon tetrachloride,
and subsequent sulfonation of (8), confirmed the synthesis of (6a). Finally
the direct conversion of (7) to (6a) in one pot was also successful (Scheme 1).
In conclusion, we present a facile one-pot synthesis of (6a) in good yield
and purity, which can serve as a template for designing new biologically active
molecules.
EXPERIMENTAL
Melting points were recorded on a Gallenkemp apparatus and are uncorrected.
1H NMR and 13C NMR spectra were recorded on a Bruker DPX-400 instrument

Facile One-Pot Synthesis
769
Scheme 1.
at 400 and 100 MHz, respectively, in DMSO unless otherwise mentioned.
Chemical shifts are reported as d in parts per million (ppm) referenced to the
residual solvent signal. IR spectra were recorded on a Perkin Elmer 1600FT
spectrometer. Mass spectra were recorded on a Jeol SX-102 instrument.

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W. A. Siddiqui et al.
Synthesis of N-Hydroxymethyl Saccharin (2)
A mixture of (1) (5 g, 27 mmol) and formaline (5 mL, 67 mmol) in water
(15 mL) was heated under reflux for 5 min,[10,11] cooled to room temperature,
and filtered. The solid was washed with cold water and dried to produce (2)
(5.4 g, 92%), mp 136–1378C (lit. 137–1418C). IR (KBr): 3280, 1745,
1175, 1055 cm21 1H NMR: d 2.05 (s, 1H), 5.19 (s, 2H), 7.92–8.26
.
(m, 4H). MS: m/z 213 (Mþ), 197, 183, 132, 120, 104, 75. Anal. calcd. for
C8H7NO4S: C, 45.07; H, 3.31; N, 6.57. Found: C, 45.05; H, 3.30; N, 6.59.
Synthesis of N-Chloromethyl Saccharin (3)
A mixture of thionyl chloride (10 mL) and (2) (5 g, 23 mmol) was heated
under reflux for 10 min under anhydrous conditions and concentrated. The
residue was dried overnight to obtain (3) (4.8 g, 89%), mp 137–1388C (lit.
1
140–1428C). IR (KBr): 1755, 1180, 1052 cm21. H NMR: d 5.25 (s, 2H),
7.84–8.10 (m, 4H). MS: m/z 233.4 (Mþ), 231.5 (Mþ), 196, 182, 118, 76.
Anal. calcd. for C8H6ClNO3S: C, 41.48; H, 2.61; N, 6.05. Found: C, 41.42;
H, 2.58; N, 6.09.
One-Step Synthesis of N-Chloromethyl Saccharin (3)
A mixture of (1) (1.72 g, 9.41 mmol), formaldehyde–sodium bisulfite adduct
(6.31 g, 47.05 mmol), and thionyl chloride (15 mL) was refluxed gently
overnight. Excess thionyl chloride was removed in vacuo, and the residue
in methylene chloride (80 mL) was washed with saturated sodium bicarbonate
(30 mL) and water (30 mL) and dried over anhydrous sodium sulfate.
Removal of the solvent yielded (3) (2.2 g, 91%), mp 137–1388C.
Synthesis of Saccharin-N-methane Sulfonic Acid (4)
N-Chloromethyl saccharin (3) (0.25 g, 1.0 mmol) and sodium iodide (0.18 g,
1.2 mmol) in acetone (25 mL) were stirred at room temperature for 15 min and
filtered. A solution of sodium sulfite (0.15 g, 1.2 mmol) in water (25 mL) was
added to the filtrate and heated under reflux (15 min). The reaction mixture
was cooled to 58C, acidified to pH 4 with 2N HCl, and concentrated in
vacuo. The resulting precipitates were filtered, washed with cold water, and
dried to give (4) (0.16 g, 45%), mp 186–1878C; IR (KBr): 3260, 1735,
1180, 1057 cm21 1H NMR: d 2.01 (s, 1H), 5.25 (s, 2H), 7.26–8.23
.
(m, 4H); 13C NMR: d 62.8, 128.1, 128.2, 128.9, 133.1, 133.9, 141.7, 169.1.
MS: m/z 277 (Mþ), 182, 139, 103, 75. Anal. calcd. for C8H7NO6S2: C,
34.65; H, 2.54; N, 5.05; S, 23.13. Found: C, 34.69; H, 2.55; N, 5.10; S, 23.05.

Facile One-Pot Synthesis
771
One-Pot Synthesis of Saccharin-N-methane Sulfonic Acid (4)
A mixture of (1) (1.72 g, 9.4 mmol), formaldehyde–sodium bisulfite adduct
(6.31 g, 47.0 mmol), and thionyl chloride (15 mL) was refluxed gently
overnight. Excess thionyl chloride was removed in vacuo, and the residue
was neutralized with ammonium hydroxide. Sodium iodide (1.55 g,
10.4 mmol) in acetone (40 mL) was added, stirred at room temperature
(20 min) along with subsequent addition of sodium sulfite (1.3 g,
10.4 mmol) in water (25 mL), and refluxed (25 min). The reaction mixture
was cooled to 58C, acidified to pH 4, and concentrated to half volume. The
resulting precipitates were filtered, washed with water, and dried to give the
product (1.28 g, 49%), mp 186–1888C.
Synthesis of Methyl [2-(Methoxycarbonyl)phenylsulfonamido]
methylsulfonate (5)
Sulfonic acid (4) (1.0 g, 3.6 mmol) was added to a solution of sodium
methoxide (0.40 g, 7.5 mmol) in dry methanol (25 mL). The reaction
mixture was heated under reflux for 15 min, cooled to room temperature,
and acidified to pH 3 with 15% HCl. The solid was filtered, washed with
cold water, and dried (408C) to produce (5) (0.97 g, 83%), mp 92–938C; IR
1
(KBr): 3450, 3295, 1680, 1175, 1050 cm21. H NMR: d 2.01 (s, 1H), 3.35
(s, 3H), 3.45 (s, 3H), 5.19 (s, 2H), 7.39–8.26 (m, 4H); 13C NMR: d 50.2,
52.1, 62.1, 128.3, 131.3, 132.0, 132.3, 134.9, 141.3, 168.1. MS: m/z 323
(Mþ), 228, 215, 135, 75. Anal. calcd. for C9H11NO7S2: C, 34.95; H, 3.58;
N, 4.53. Found: C, 34.88; H, 3.53; N, 4.49.
Synthesis of Methyl 4-Hydroxy-2-methyl-(2H)-1,2-benzothiazine-3-
sulfonate 1,1-Dioxide (6)
In a flame-dried, three-neck, round-bottom flask, under an N2 atmosphere,
sodium hydride (1.2 g, 24 mmol, 50% dispersion) was placed. The mineral
oil was removed by hexane washing, followed by addition of (5) (1.85 g,
6.0 mmol) in DMF (20 mL). The mixture was heated to 408C (30 min) and
brought to room temperature. Methyl iodide (0.4 mL, 6.4 mmol) in DMF
(10 mL) was added to the reaction mixture and stirred for an additional
30 min. The precipitates obtained after acidification to pH 3 with 5% HCl
were washed and dried to get (6) (0.23 g, 23%), mp 219–2208C. IR (KBr):
1
3320, 3290, 1175, 1050 cm21. H NMR: d 3.25 (s, 3H), 3.75 (s, 3H), 7.21–
8.10 (m, 4H), 11.05 (s, 1H); 13C NMR: d 34.5, 52.7, 95.3, 127.7, 128.1,
129.3, 129.9, 132.2, 138.6, 162.1. MS: m/z 305 (Mþ), 210, 178 107, 75.
Anal. calcd. for C9H9NO6S2: C, 37.11; H, 3.11; N, 4.81; S, 22.02. Found:
C, 37.09; H, 3.10; N, 4.82; S, 22.07.

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W. A. Siddiqui et al.
Synthesis of 3-Bromo-3,4-dihydro-2-methyl-4-oxo-2H-1,2-
benzothiazine 1,1-Dioxide (8)
A mixture of(7)(2.1 g, 9.9 mmol), N-bromosuccinimide(1.9 g, 11.0 mmol), and
azoisobutyronitrile (0.01 g) in carbon tetrachloride (25 mL) was heated under
reflux (1 h), cooled to room temperature, and filtered. Evaporation of the
solvent under reduced pressure afforded a solid, which was recrystallized from
ethanol–diethyl ether (50:50) to get (8) (2.2 g, 75%), mp 72–738C. IR (KBr):
1680, 1180, 1055 cm21. 1H NMR (CDCl3): d 2.21 (s, 1H), 3.11 (s, 3H), 7.22–
8.10 (m, 4H); 13C NMR (CDCl3): d 32.4, 79.9, 128.2, 130.7, 130.8, 132.7,
134.4, 140.1, 194.5. MS: m/z 290 (Mþ), 210, 165, 101, 75. Anal. calcd. for
C9H8BrNO3S: C, 37.26; H, 2.78; N, 4.83. Found: C, 37.22; H, 2.71; N, 4.82.
Synthesis of 4-Hydroxy-2-methyl-(2H)-1,2-benzothiazine-3-sulfonic
Acid 1,1-Dioxide (6a)
A mixture of (8) (2.5 g, 8.6 mmol) and sodium iodide (1.4 g, 9.5 mmol) in
acetone (50 mL) was stirred at room temperature (30 min) and filtered.
Sodium sulfite (1.2 g, 9.5 mmol) in water (50 mL) was added to the filtrate
and stirred at 408C (4 h). The reaction mixture was cooled to 58C, acidified
to pH 4, and concentrated in vacuo. The precipitates were filtered, washed
with cold water, and dried to get (6) (1.3 g, 53%), mp 228–2298C. IR
(KBr): 3320, 3275, 1180, 1057 cm21 1H NMR: d 2.01 (s, 1H), 3.25
.
(s, 3H), 7.20–8.15 (m, 4H), 11.03 (s, 1H); MS: m/z 291 (Mþ), 210, 178, 75.
One-Pot Synthesis of 4-Hydroxy-2-methyl-(2H)-1,2-benzothiazine-
3-sulfonic Acid 1,1-Dioxide (6a)
A mixture of (7) (2.1 g, 9.9 mmol), N-bromosuccinimide (1.9 g, 11.0 mmol),
and azoisobutyronitrile (0.01 g) in carbon tetrachloride (20 mL) was heated
under reflux (1 h) and cooled to room temperature. Sodium iodide (1.64 g,
10.9 mmol) in acetone (25 mL) was added and stirred (15 min), followed by
addition of sodium sulfite (1.38 g, 10.9 mmol) in water (45 mL). The
reaction mixture was heated under reflux (30 min), cooled, and filtered, and
the filtrate was acidified to pH 4 with 2N HCl. The solution was concentrated,
and precipitates were filtered, washed with cold water, and dried to give the
product (2.9 g, 41%), mp 228–2308C.
ACKNOWLEDGMENTS
We greatly acknowledge the Higher Education Commission of Pakistan,
Islamabad, for financial support, as well as Loughborough University for

Facile One-Pot Synthesis
773
providing analytical facilities. We thank John C. Kershaw for running mass
spectra and J. Alastair Daley for elemental analysis.
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